Various publications or patents are referred to throughout this application or at the end of this specification to describe the state of the art to which the invention pertains. Each of these publications or patents is incorporated by reference herein.
Infertility is a disease that results in the abnormal functioning of the human reproductive system. It is defined as the inability to conceive after one year of unprotected intercourse or the inability to carry a pregnancy to live birth. According to the Centers for Disease Control (CDC), 2.1 million married couples suffer from infertility or other conditions that impair their ability to have children, and an estimated 6.1 million women of child bearing age in the United States are infertile.
Female fertility begins to decline many years prior to the onset of menopause despite continued regular ovulatory cycles. Although there is no precise definition of advanced reproductive age in women, infertility is more prevalent after the age of 35. Because the average age of childbearing has increased over the past thirty years as more women have pursued higher education and careers, an unprecedented number of women will have reached their late reproductive years by the time they are ready to start families. As a consequence, many will require the assistance of fertility treatments in order to conceive a child. With patients willing to invest thousands of dollars in treatments to fulfill their dreams of starting a family, infertility has become a $2 billion industry annually in the US.
With the exception of oocyte donation, all fertility treatments currently available to women unable to conceive naturally depend on the woman's ovarian reserve. The term “ovarian reserve” refers to a woman's current supply of ovarian follicle number and oocyte quality, and is closely associated with reproductive potential. In general, the greater the number of remaining eggs, the better the chance for conception. Conversely, low ovarian reserve greatly diminishes a patient's chances for conception. As a woman ages, her supply of eggs gradually declines over time until the eggs are depleted at menopause. Even before birth, a woman's eggs begin to diminish in number. The great majority of oocytes are lost after the fifth month of intrauterine life, when a maximum of about seven million eggs have been reported. At birth, both ovaries contain around one million primordial follicles. Reproductive life starts with approximately 0.5 million primordial follicles at menarche. Thereafter, loss of follicles takes place at a fixed rate of around 1000 per month, accelerating beyond the age of 35. The number of eggs continues to decline as the woman ages, until no eggs remain at the time of menopause.
The most important aspect of diminished ovarian reserve, and the associated decline in reproductive potential, is that its onset is highly variable. Ovarian function is unique for each individual, both in the number of years of peak reproductive performance as well as in the onset and progression of its decline. Some women with normal menstrual cycles will have difficulty conceiving in their late twenties or early thirties. Because of the high individual variability of ovarian status, it is vitally important for clinicians to assess an infertility patient's ovarian reserve. In fact, the assessment of a woman's ovarian reserve is one of the most critical factors in the infertility evaluation of patients of any age. Women with diminished ovarian reserve experience decreased responses to ovulation induction, require higher doses of gonadotropin, have higher IVF (In Vitro Fertilization) cycle cancellation rates, and experience lower pregnancy rates through IVF.
Currently available methods for assessing ovarian reserve can be classified into passive and dynamic tests. The goal of both approaches is to provide information regarding oocyte quality and quantity in order to assess whether a woman is a candidate for a particular course of infertility treatment. The standard passive test for ovarian reserve consists of the measurement of serum basal FSH and estradiol on day 3 of the menstrual cycle. An early follicular phase FSH level of less than 10 mIU/ml and an estradiol level of less than 80 pg/ml is typically considered indicative of normal ovarian reserve, although cutoff values for FSH as high as 20 to 25 mIU/ml have been reported because of the use of different FSH assay reference standards. It is difficult to establish absolute values that define how high FSH levels can be due to variations in laboratory assessments and treatment methods. Moreover, women with baseline values in the normal range may have diminished reserves and by the time an elevation in the FSH level is evident it could well be too late for them to achieve a pregnancy or have fertility treatment. Some women with a normal FSH can be completely unaware that their ovarian reserve is steadily declining and are lulled into a false sense of security with regard to their prospects of starting a family. Other passive tests of ovarian reserve are under investigation but have not yet been recommended for routine clinical use because of limited data on their prognostic value. In contrast to the static measurements of ovarian reserve, the clomiphene citrate challenge test (CCCT) is a dynamic approach. Its purpose is to stimulate the ovary to initiate egg production in response to the fertility drug clomiphene. Although the clomiphene citrate challenge test is generally considered to be more accurate than the basal serum FSH test, none of the currently available tests have been shown to accurately reflect ovarian reserve.
It is thus evident that there is a need for more accurate and reliable methods of predicting and monitoring a woman's response to infertility treatment. In addition, a new method that would prevent the depletion of ovarian reserve would be highly desirable in the field of reproductive technology.